Reputedly born around 566, Derfel is said to be one of seven warriors of Arthur who survived the Battle of Camlan. Three of the six other survivors were also said to have become saints. While others survived through good fortune, Derfel survived "by his strength alone".

Derfel is said to have been a noted warrior in medieval Welsh poetry. Tudur Penllyn wrote:

"When there were at Camlan men and fighting and a host being slain, Derfel with his arms was dividing steel there in two".

After Camlan, Derfel is unanimously held in Welsh tradition to have entered the religious life. After a possible stint as a hermit, he is said to have entered the monastery of Llantwit. He was also associated with Llandderfel in Gwynedd, named after and said to have founded by him. He is also said to have served as the abbot of Ynys Enlli, Bardsey Island, succeeding his cousin St. Cadfan. He is said to have died of natural causes on April 6, 660.

For centuries Derfel was venerated at the churches of Llanfihangel Llantarnam, which claimed a relic of him, and Llandderfel, which featured a wooden image of him; he was an object of pilgrimage at these sites. Derfel was depicted as a warrior in full armour riding a horse rather than as an ecclesiastic. The Llandderfel image was removed and dismantled by order of Thomas Cromwell during the English Reformation and used to burn a Catholic priest, John Forest, at Smithfield in London. This was held to be a fulfillment of a prophecy that the image would burn down a forest. Part of the image survives to the present day at Llandderfel.